A Novel Small-Molecule Inhibitor of SREBP-1 Based on Natural Product Monomers Upregulates the Sensitivity of Lung Squamous Cell Carcinoma Cells to Antitumor Drugs

De-Bin Ma; Xing-Yu Liu; Hui Jia; Yingshi Zhang; Qiyu Jiang; Huiwei Sun; Xiaojuan Li; Fang Sun; Yantao Chai; Fan Feng; Lei Liu

doi:10.3389/fphar.2022.895744

A Novel Small-Molecule Inhibitor of SREBP-1 Based on Natural Product Monomers Upregulates the Sensitivity of Lung Squamous Cell Carcinoma Cells to Antitumor Drugs

Front Pharmacol. 2022 May 18:13:895744. doi: 10.3389/fphar.2022.895744. eCollection 2022.

Authors

De-Bin Ma¹, Xing-Yu Liu², Hui Jia³, Yingshi Zhang⁴, Qiyu Jiang⁵, Huiwei Sun⁵, Xiaojuan Li⁵, Fang Sun⁵, Yantao Chai⁶, Fan Feng⁶, Lei Liu¹

Affiliations

¹ Department of Respiratory and Critical Care Medicine, General Hospital of Northern Theater Command, Shenyang, China.
² Department of General Internal Medicine, Central Medical Branch of PLA General Hospital, Beijing, China.
³ School of Traditional Chinese Medicine, Shenyang Medical College, Shenyang, China.
⁴ Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.
⁵ Institute of Infectious Diseases, Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
⁶ Department of Clinical Laboratory, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.

Abstract

The transcription factor, sterol regulatory element binding protein 1 (SREBP-1), plays important roles in modulating the proliferation, metastasis, or resistance to antitumor agents by promoting cellular lipid metabolism and related cellular glucose-uptake/Warburg Effect. However, the underlying mechanism of SREBP-1 regulating the proliferation or drug-resistance in lung squamous cell carcinoma (LUSC) and the therapeutic strategies targeted to SREBP-1 in LUSC remain unclear. In this study, SREBP-1 was highly expressed in LUSC tissues, compared with the paired non-tumor tissues (the para-tumor tissues). A novel small-molecule inhibitor of SREBP-1, MSI-1 (Ma's inhibitor of SREBP-1), based on natural product monomers, was identified by screening the database of natural products. Treatment with MSI-1 suppressed the activation of SREBP-1-related pathways and the Warburg effect of LUSC cells, as indicated by decreased glucose uptake or glycolysis. Moreover, treatment of MSI-1 enhanced the sensitivity of LUSC cells to antitumor agents. The specificity of MSI-1 on SREBP-1 was confirmed by molecular docking and point-mutation of SPEBP-1. Therefore, MSI-1 improved our understanding of SREBP-1 and provided additional options for the treatment of LUSC.

Keywords: Warburg effect; antitumor agents; lung squamous cell carcinoma; natural product monomers; small molecular inhibitor; sterol regulatory element binding protein 1.